The nociceptin receptor ORL-1 has been shown to be involved with modulation of pain in animal models. ORL-1 (the nociceptin receptor) was discovered as an xe2x80x9corphan opioid-like receptorxe2x80x9d i.e. a receptor whose ligand was unknown. The nociceptin receptor is a G protein coupled receptor. While highly related in structure to the three classical opioid receptors, i.e. the targets for traditional opioid analgesics, it is not activated by endogenous opioids. Similarly, endogenous opioids fail to activate the nociceptin receptor. Like the classical opioid receptors, the nociceptin receptor has a broad distribution in the central nervous system.
In late 1995, nociceptin was discovered and shown to be an endogenous peptide ligand that activates the nociceptin receptor. Data included in the initial publications suggested that nociceptin and its receptor are part of a newly discovered pathway involved in the perception of painful stimuli. Subsequent work from a number of laboratories has shown that nociceptin, when administered intraspinally to rodents, is an analgesic. The efficacy of nociceptin is similar to that of endogenous opioid peptides. Recent data has shown that nociceptin acts as an axiolytic when administered directly into the brain of rodents. When tested in standard animals models of anxiety, the efficacy of nociceptin is similar to that seen with classical benzodiazapine anxiolytics. These data suggest that a small molecule agonist of the nociceptin receptor could have significant analgesic or anxiolytic activity.
Additional recent data (Rizzi, et al, Life Sci., 64, (1999), p. 157-163) has shown that the activation of nociceptin receptors in isolated guinea pig bronchus inhibits tachykinergic non adrenergic-non cholinergic contraction, indicating that nociceptin receptor agonists could be useful in the treatment of asthma. Also, it has been reported (Ciccocioppo et al, Physchpharmacology, 141 (1999), p. 220-224) nociceptin reduces the rewarding properties of ethanol in msP alcohol preferring rats, suggesting that intervention of nociceptin could be useful in the treatment of alcohol abuse. In EP 856,514, 8-substituted 1,3,8-triazaspiro[4,5]decan-4-on derivatives were disclosed as agonists and/or antagonists of orphanin FQ (i.e., nociceptin) useful in the treatment of various disorders, including depression; 2-oxoimidazole derivatives disclosed in WO98/54168 were described as having similar utility. Earlier, benzimidazolyl piperidines were disclosed in U.S. Pat. No. 3,318,900 as having analgesic activity.
Potent analgesic agents such as traditional opioids, e.g. morphine, carry with them significant side-effects. Clinically relevant side-effects include tolerance, physical dependence, respiratory depression and a decrease in gastrointestinal motility. For many patients, particularly those subjected to chronic opioid therapy, i.e. cancer patients, these side effects limit the dose of opioid that can be administered. Clinical data suggests that more than one-third of cancer patients have pain which is poorly controlled by present agents. Data obtained with nociceptin suggest the potential for advantages over opioids. When administered chronically to rodents, nociceptin, in contrast to morphine, showed no addiction liability. Additionally, chronic morphine treatment did not lead to a xe2x80x9ccross-tolerancexe2x80x9d to nociceptin, suggesting that these agents act via distinct pathways.
In view of the current interest in pain relief, a welcome contribution to the art would be additional compounds useful for modifying the effect of nociceptin, a natural ligand to ORL-1 and therefore useful in the management of pain and anxiety. Such a contribution is provided by this invention.
Compounds of the present invention are represented by formula I 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
the dotted line represents an optional double bond;
X1 is R5xe2x80x94(C1-C12)alkyl, R6xe2x80x94(C3-C12)cycloalkyl, R7-aryl, R8-heteroaryl or R10xe2x80x94(C3-C7)heterocycloalkyl;
X2 is xe2x80x94CHO, xe2x80x94CN, xe2x80x94NHC(xe2x95x90NR26)NHR26, xe2x80x94CH(xe2x95x90NOR26), xe2x80x94NHOR26, R7-aryl, R7-aryl(C1-C6)alkyl, R7-aryl(C1-C6)-alkenyl, R7-aryl(C1-C6)-alkynyl, (CH2)vOR13, xe2x80x94(CH2)vCOOR27, xe2x80x94(CH2)vCONR14R15, xe2x80x94(CH2)vNR21R22 or xe2x80x94(CH2)vNHC(O)R21, wherein v is zero, 1, 2 or 3 and wherein q is 1 to 3 and a is 1 or 2;
or X1 is 
and
X2 is hydrogen;
or X1 and X2 together form a spiro group of the formula 
m is 1 or 2;
n is 1, 2 or 3, provided that when n is 1, one of R16 and R17 is xe2x80x94C(O)R28;
p is 0 or 1;
Q is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR17xe2x80x94;
R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or (R1 and R4) or (R2 and R3) or (R1 and R3) or (R2 and R4) together can form an alkylene bridge of 1 to 3 carbon atoms;
R5 is 1 to 3 substituents independently selected from the group consisting of H, R7-aryl, R6xe2x80x94(C3-C12)cycloalkyl, R8-heteroaryl, R10xe2x80x94(C3-C7)heterocycloalkyl, xe2x80x94NR19R20, xe2x80x94OR13 and xe2x80x94S(O)0-2R13;
R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R7-aryl, xe2x80x94NR19R20, xe2x80x94OR13 and xe2x80x94SR13;
R7 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R25-aryl, (C3-C12)cycloalkyl, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR19, xe2x80x94(C1-C6)alkyl-OR19, xe2x80x94OCF3, xe2x80x94NR19R20, xe2x80x94(C1-C6)alkyl-NR19R20, NHSO2R19, SO2N(R26)2, xe2x80x94SO2R19, xe2x80x94SOR19, xe2x80x94SR19, xe2x80x94NO2, xe2x80x94CONR19R20, xe2x80x94NR20COR19, xe2x80x94COR19, xe2x80x94COCF3, xe2x80x94OCOR19, xe2x80x94OCO2R19, xe2x80x94COOR19, xe2x80x94(C1-C6)alkyl-NHCOOC(CH3)3, (C1-C6)alkyl-NHCOCF3, xe2x80x94(C1-C6)alkyl-NHSO2xe2x80x94(C1-C6)alkyl, xe2x80x94(C1-C6)alkyl-NHCONHxe2x80x94(C1-C6)-alkyl or 
wherein f is 0 to 6; or R7 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R25-aryl, (C3-C12)cycloalkyl, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR19, xe2x80x94(C1-C6)alkyl-OR19, xe2x80x94OCF3, NR19R20, xe2x80x94(C1-C6)alkyl-NR19R20, xe2x80x94NHSO2R19, xe2x80x94SO2N(R26)2, xe2x80x94NO2, xe2x80x94CONR19R20, NR20COR19, xe2x80x94COR19, xe2x80x94OCOR19, xe2x80x94OCO2R19 and xe2x80x94COOR19;
R9 is hydrogen, (C1-C6)alkyl, halo, xe2x80x94OR19, xe2x80x94NR19R20, xe2x80x94NHCN, xe2x80x94SR19 or (C1-C6)alkyl-NR19R20;
R10 is H, (C1-C6)alkyl, xe2x80x94OR19, xe2x80x94(C1-C6)alkyl-OR19, xe2x80x94NR19R20 or xe2x80x94(C1-C6)alkyl-NR19R20;
R11 is independently selected from the group consisting of H, R5xe2x80x94(C1-C6)alkyl, R6xe2x80x94(C3-C12)cycloalkyl, xe2x80x94(C1-C6)alkyl(C3-C12)cycloalkyl, xe2x80x94(C1-C6)alkyl-OR19, xe2x80x94(C1-C6)alkyl-NR19R20 and 
wherein q and a are as defined above;
R12 is H, (C1-C6)alkyl, halo, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OR19, xe2x80x94(C1-C6)alkyl-OR19, xe2x80x94NR19R20 or xe2x80x94(C1-C6)alkyl-NR19R20;
R13 is H, (C1-C6)alkyl, R7-aryl, xe2x80x94(C1-C6)alkyl-OR19, xe2x80x94(C1-C6)alkyl-NR19R20; xe2x80x94(C1-C6)alkyl-SR19; or aryl (C1-C6) alkyl;
R14 and R15 are independently selected from the group consisting of H, R5xe2x80x94(C1-C6)alkyl, R7-aryl and 
wherein q and a are as defined above;
R16 and R17 are independently selected from the group consisting of hydrogen, R5xe2x80x94(C1-C6)alkyl, R7-aryl, (C3-C12)cycloalkyl, R8-heteroaryl, R8-heteroaryl(C1-C6)alkyl, C(O)R28, xe2x80x94(C1-C6)alkyl(C3-C7)-heterocycloalkyl, xe2x80x94(C1-C6)alkyl-OR19 and xe2x80x94(C1-C6)alkyl-SR19;
R19 and R20 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;
R21 and R22 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, (C3-C12)cycloalkyl(C1-C6)alkyl, (C3-C7)heterocycloalkyl, xe2x80x94(C1-C6)alkyl(C3-C7)heterocycloalkyl, R7-aryl, R7-aryl(C1-C6)alkyl, R8-heteroaryl(C1-C12)alkyl, (C1-C6)alkyl-OR19xe2x80x94(C1-C6)alkyl-NR19R20, xe2x80x94(C1-C6)alkyl-SR19, xe2x80x94(C1-C6)alkyl-NR18xe2x80x94(C1-C6)alkyl-Oxe2x80x94(C1-C6)alkyl and xe2x80x94(C1-C6)alkyl-NR18xe2x80x94(C1-C6)alkyl-NR18xe2x80x94(C1-C6)alkyl;
R18 is hydrogen or (C1-C6)alkyl;
Z1 is R5xe2x80x94(C1-C12)alkyl, R7-aryl, R8-heteroaryl, R6xe2x80x94(C3-C12)cyclo-alkyl, R10xe2x80x94(C3-C7)heterocycloalkyl, xe2x80x94CO2(C1-C6)alkyl, CN or xe2x80x94C(O)NR19R20; Z2 is hydrogen or Z1; Z3 is hydrogen or (C1-C6)alkyl; or Z1, Z2 and Z3, together with the carbon to which they are attached, form the group 
wherein r is 0 to 3; w and u are each 0-3, provided that the sum of w and u is 1-3; c and d are independently 1 or 2; s is 1 to 5; and ring A is a fused R7-phenyl or R8-heteroaryl ring;
R23 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, xe2x80x94OR19, xe2x80x94(C1-C6)alkyl-OR19, -NR19R20 and xe2x80x94(C1-C6)alkyl-NR19R20;
R24 is 1 to 3 substituents independently selected from the group consisting of R23, xe2x80x94CF3, xe2x80x94OCF3, NO2 or halo, or R24 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
R25 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;
R26 is independently selected from the group consisting of H, (C1-C6)alkyl and R25xe2x80x94C6H4xe2x80x94CH2xe2x80x94;
R27 is H, (C1-C6)alkyl, R7-aryl(C1-C6)alkyl, or (C3-C12)cycloalkyl;
R28 is (C1-C6)alkyl, xe2x80x94(C1-C6)alkyl(C3-C12)cycloalkyl, R7-aryl, R7-aryl-(C1-C6)alkyl, R8-heteroaryl, xe2x80x94(C1-C6)alkyl-NR19R20, xe2x80x94(C1-C6)alkyl-OR19 or xe2x80x94(C1-C6)alkyl-SR19;
provided that when X1 is 
or X1 and X2 together are 
and Z1is R7-phenyl, Z2 is not hydrogen or (C1-C3)alkyl;
provided that when Z1, Z2 and Z3, together with the carbon to which they are attached, form 
and X1 and X2 together are 
R11 is not H, (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)hydroxyalkyl;
provided that when R2 and R4 form an alkylene bridge, Z1, Z2 and Z3, together with the carbon to which they are attached, are not
provide that when X1 is 
provided that when X1 is 
and Z1 is R6xe2x80x94(C3-C12)-cycloalkyl, Z2 is not H.
Preferred compounds of the invention are those wherein Z1and Z2 are each R7-aryl, particularly R7-phenyl. Preferred R7 substituents are (C1-C6)alkyl and halo, with ortho-substitution being more preferred.
Compounds wherein R1, R2, R3 and R4 are each hydrogen are preferred, as well as compounds wherein R1 and R3 are each hydrogen and R2 and R4 are an alkylene bridge of 2 or 3 carbons.
Preferred are compounds wherein X1 is R7-aryl, for example R7-phenyl, and X2 is OH (i.e., X2 is xe2x80x94(CH2)vOR13, wherein v is 0 and R13 is H) or xe2x80x94NC(O)R28, compounds wherein X1 is 
wherein R12 is hydrogen and R11 is (C1-C6)alkyl, xe2x80x94(C1-C6) alkyl(C3-C12)cycloalkyl, xe2x80x94(C1-C6)alkyl-OR19 or xe2x80x94(C1-C6)alkyl-NR19R20; and compounds wherein X1 and X2 together form the spirocyclic group 
wherein m is 1, R17 is phenyl and R11 is xe2x80x94(C1-C6)alkyl-OR19 or xe2x80x94(C1-C6)alkyl-NR19R2, or 
In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.
The compounds of the present invention are agonists and/or antagonists of the ORL-1 receptor, and therefore, in another aspect, the invention relates to a method of treating pain, anxiety, cough, asthma, alcohol abuse or depression, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I.
In another aspect, the invention relates to a method of treating cough, comprising administering to a mammal in need of such treatment: (a) an effective amount of a nociceptin receptor ORL-1 agonist; and (b) an effective amount of a second agent for treating cough, allergy or asthma symptoms selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, xcex2-adrenergic receptor agonists, xanthine derivatives, xcex1-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.
In still another aspect, the invention relates to a pharmaceutical composition comprising a nociceptin receptor ORL-1 agonist and a second agent selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, xcex2-adrenergic receptor agonists, xanthine derivatives, xcex1-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.
In yet another aspect, the present invention relates to a novel compound not included in the structure of formula I, said compound being: 